1. Field of the Invention
The present invention relates to a novel, essentially enantiomerically pure diarylmethylpiperazine compound having utility as a receptor-binding species, e.g., as a mu and/or delta receptor opioid compound for use as an analgesic and as a therapeutic agent having utility in combating drug addiction, alcohol addiction, cardiac disorders, drug overdose, mental illness, cough, lung edema, diarrhea, respiratory, and gastro-intestinal disorders.
2. Description of Related Art
In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds have been identified. Opioid drugs typically are classified by their binding selectivity in respect of the cellular and differentiated tissue receptors to which a specific drug species binds as a ligand. These receptors include mu (μ), delta (δ), sigma (σ) and kappa (κ) receptors.
The well-known narcotic opiates, such as morphine and its analogs, are selective for the opiate mu receptor. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal transit; kappa receptors mediate analgesia and sedation: and sigma receptors mediate various biological activities.
The existence of the opioid delta receptor is a relatively recent discovery, which followed the isolation and characterization of endogenous enkephalin peptides that are ligands for the delta receptor. Research in the past decade has produced significant information about the delta receptor. Delta receptors mediate analgesia, but do not appear to inhibit intestinal transit in the manner characteristic of mu receptors.
Opioid diarylmethylpiperazines having both mu and delta receptor activity have been described in U.S. Pat. No. 5,658,908 (Chang et al.). However, the synthesis of these compounds in the laboratory, having at least one asymmetric carbon atom, invariably leads to a racemic mixture exhibiting no optical activity. In contrast, naturally occurring compounds that possess an asymmetric carbon atom almost invariably are optically active.
In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (−) or d and l are employed to designate the direction of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
Whereas the foregoing Chang et al. patent recognized that diarylmethylpiperazines may have optically active forms and individual enantiomeric forms may be synthesized, no example of the presently claimed optically active form was given. Although it was generally concluded heretofore that the described diarylmethylpiperazines racemic mixtures and inclusive enantiomers exhibited similar activity, it has been discovered by the present inventor that there are substantial unforeseen advantages in the use of the presently claimed enantiomerically pure diarylmethylpiperazine for use in cardioprotection, and particularly for effectuating and/or mimicing the results of ischemic preconditioning.
Ischemic preconditioning (PC) is a phenomenon, widely demonstrated in many species, including man, whereby the myocardium is protected from a major ischemic event by prior brief periods of ischemia or hypoxia followed by reperfusion or reoxygenation. The use of short-duration, transient ischemia to protect against damage from a subsequent and more prolonged ischemic event has been demonstrated by Murry, et al. (Circulation, 1986: 74: 1124–1136). Test results show a reduction of tissue necrosis by approximately 30% in canine hearts that have been pretreated with short periods of ischemia prior to a major long-term event. The phenomenon of ischemic preconditioning has become of great clinical interest for treatment of patients with ischemic heart disease.
It has been determined that a number of membrane receptors are involved in preconditioning including opioid receptors. The three main opioid receptor subtypes are μ, κ and δ. Delta opioid receptor stimulation mimics natural hibernation even in non-hibernating animals and has been reported to enhance tissue survival when oxygen delivery to the tissue is minimal. As such, delta opioid receptor stimulation has been shown to be involved in ischemic preconditioning. A number of studies have been conducted using peptidic and non-peptidic delta opioid receptor agonists to induce the effects of ischemic preconditioning. Schultz and Gross (U.S. Pat. No. 6,103,722) tested numerous non-peptidic delta opioid receptor compounds that exhibited ischemic preconditioning-like effects including (−)-2-Methyl-4a.α-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a.β-octahydroquinolino [2,3] isoquinoline (TAN67); (±)-4-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N diethylbenzamide (BW373U86); and (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3methoxybenzyl]-N,N -diethylbenzamide (SNC80).
However, these non-peptidic compounds are not without problems due to the possibility of causing seizures. Thus, it is desirable to have a treatment that effectuates ischemic preconditioning by pharmacological means, which avoids the problems associated with reduced blood supply to the cardiac muscle and the potential of seizures caused by administration of some delta opioid receptor agonist compounds.